Unlike other tissue which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system. Glutamate (Glu) is an endogenous amino acid which was early characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normally, glutamate is maintained at relatively high concentrations within brain tissue cells by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, these cells can release glutamate and under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockade of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J.W. Olney, "Glutamate and the Pathophysiology of Hypoxia-Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS). Glutamate is believed to be a mixed agonist capable of binding to and exciting all three receptor types.
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
Certain oxobarbiturate and thiobarbiturate compounds, including thiopentone (thiopental), have been studied for their convulsant, anticonvulsant and anesthetic properties, with both series of barbiturates found to have the same qualitative activities [P. R. Andrews, et al., Eur. J. Pharmacol., 79, 61-65 (1982)]. High-dose barbiturate treatment, with compounds such as thiopental, pentobarbital and phenobarbitol, has been reported as a potentially beneficial approach to clinical management of cerebral anoxia-ischemia [J. H. Piatt, Jr., et al. Neurosurgery, Vol. 15, No. 3, 427-444 (1984)]. Glutamate antagonists have been used in various animal models to treat epilipsy-related conditions [B. Meldrum Clinical Sci., 68, 113-122 (1985)].
It is known that certain barbiturates protect the ex vivo chick embryo retina from the excitotoxic activity of either N-methyl aspartate (NMA) or kainic acid (KA). For example, barbiturates such as aprobarbital, phenobarbital, pentothal, seconal and amytal have been shown to possess anti-excitotoxic activity, with seconal having the most potency. The anti-excitotoxic actions of barbiturates in the chick embryo retina cannot readily be attributed to an action through the gamma-aminobutyric acid (GABA) system since GABA itself, in very high concentrations, does not protect retinal neurons against the toxic actions of NMA, KA or GLu. ThE acute anti-excitotoxic properties of several short-acting barbiturates (methohexital, thiopental, thiamylal) have been demonstrated in the ex vivo chick embryo retina. It is believed that because of such anti-excitotoxic properties, these short-acting barbiturates prevent KA from causing seizures and seizure-related brain damage (SRBD) in the in vivo rat.
Other classes of compounds have been tested as agonists in blocking NMDA- or KA-induced neurotoxicity [J. W. Olney eT al., "The Anti-Excitotoxic Effects of Certain Anesthetics, Analgesics and Sedative-Hypnotics, " Neuroscience Letters, 68, 29-34 (1986)]. The tested compounds included phencylidine, ketamine, cyclazocine, kynurenate and various barbiturates such as secobarbital, amobarbital and pentobarbital. None of the tested compounds was reported as a broad spectrum antagonist effective in blocking the neurotoxic actions of NMA, KA, quisqualate and glutamate.